PTSD is common, severe, and disabling, and depression and insomnia are often prominent features. The best-established treatments for PTSD are cognitive behavioral therapies (CBT), but some patients prefer medication treatment, trained CBT therapists are not available in all areas, and CBT is not always effective. The selective serotonin reuptake inhibitors (SSRIs) are the best-established medication treatment, but they are of modest efficacy. High dropout rates, delayed response, relatively poor treatment of insomnia, and sexual adverse effects are common drawbacks to SSRIs, although there is evidence that patients who are able to continue SSRI treatment for up to 36 weeks achieve high rates of response. More-effective medication treatments are urgently needed for PTSD. One approach to improving medication treatment of PTSD is to build upon the known partial efficacy of SSRIs by developing a combination treatment strategy that counteracts the limitations of SSRIs. An ideal augmenting agent would be a medication that when initiated with an SSRI improves acceptability, tolerability and efficacy by: 1) accelerating time to response; 2) enhancing overall response; 3) improving PTSD-related insomnia and sexual dysfunction, and counteracting common side effects of SSRIs, such as insomnia and sexual dysfunction; and 4) being safe to administer with an SSRI. Mirtazapine is a marketed antidepressant with antagonist at serotonin 5HT2 and 5HT3, 2-adrenergic and histamine H1 receptors, and it meets each of the above criteria for a potential augmenter of SSRI treatment for PTSD through additive and synergistic mechanisms. This combination is novel to PTSD, and its safety and high acceptability has been documented in other disorders and in nonclinical samples. The overall goal of this study is to examine feasibility, acceptability, safety, efficacy and risk/benefit ratio of combined mirtazapine and SSRI treatment for PTSD in a placebo-controlled trial. Results will inform whether combined mirtazapine and SSRI treatment is suitable for larger-scale study of its efficacy, effectiveness, and mechanisms of action, and will establish methods to be used in such studies. This proposal addresses NIMH Strategic Plan goals of developing innovative interventions that examine the balance between adverse effects and beneficial effects of interventions and examine how to minimize side effects. The long-term goal is to improve the treatment outcome of PTSD by developing new and advantageous pharmacological treatment strategies. In this study, 60 patients with civilian PTSD will be randomized to 24 weeks of double-blind treatment with sertraline + mirtazapine versus sertraline + placebo. Patients who show at least a minimal response after 12 weeks will continue for another 12 weeks on the same double-blind study treatment. Outcome will be assessed by independent assessors, treating psychiatrists and patients. Outcome measures will include ratings of severity of PTSD, insomnia, and depression symptoms; response and remission; dropout and duration of persistence in treatment, quality of life, and adverse effects, including assessment of sexual functioning. Improvement will be assessed over the first 12 weeks of treatment, and over the full 24 weeks. PUBLIC HEALTH RELEVANCE: PTSD is common, severe, and disabling. The SSRIs are the best-established medication treatment, but they are of modest efficacy. This study examines a strategy for augmenting the effect of treatment with the SSRI sertraline, by combining it with another antidepressant mirtazapine, or placebo, over 24 weeks of treatment.